8/19- Inherited Bleeding Disorders Flashcards Preview

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Flashcards in 8/19- Inherited Bleeding Disorders Deck (59)
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1

What is the first step of hemostasis?

Injury to the endothelium allows blood to come into contact with the subendothelium

- Injury exposes tissue factor bearing cells and collagen, which VWF binds to

2

VWF binds to what? Why?

VWF binds to collagen and tethers circulating platelets -> Platelet adhesion

3

After ahesion, platelets get activated and release what?

This results in what?

- Thromboxane

- Serotonin

- ADP

Results in:

- Vasoconstriction

- Attract and cause platelets to stick to each other (platelet aggregation) forming a platelet plug

- Promote blood clotting

4

On what factors does primary hemostasis depend?

Subendothelium

- Normal collagen

- Tissue factor

Von Willebrand factor

- Normal amt and function

Platelets

- Need adequate number and function

5

What is secondary hemostasis?

The formation of insoluble, cross-linked fibrin (factor Ia) by activated clotting factors (thrombin, factor IIa)

- 2 pathways: extrinsic and intrinsic

- Stabilizes the primary platelet plug

6

Clotting factors (table)

7

Intrinsic pathway involves which factors? Extrinsic?

Intrinsic: 12, 11, 9, 8

Extrinsic: TF, 7

8

Prothrombin to thrombin conversion depends on what coagulation factor?

FIIa (2a)

9

Overview/organizational breakdown of inherited bleeding disorders (1' vs. 2')

Primary hemostasis

- Von Willebrand disease (VWD)

Secondary hemostasis

- Hemphilia A

- Hemophilia B

10

What is the prothrombin-ase complex? What does it do?

Prothrombin-ase = TF + FVIIa

- Converts promthrombin to thrombin (FIIa)

11

What is X-ase complex? What does it do?

X-ase = FVIIIa + FIXa (8 and 9)

- Activates FX (10)

12

Case)

- 4 yo male with frequent nosebleeds

What do we want to know?

- Localized vs. systemic?

- Frequency and duration

- Onset: spontaneous vs. surgery

- Other bleeding symptoms

- Systemic dz?

- Medications: aspirin, warfarin...

- Family Hx?

13

What are cinical features associated with primary hemostasis? Secondary hemostasis?

Primary hemostasis

- Mucosal bleeding (e.g. nosebleeds, menorrhagia, petechiae, prolonged after tooth extraction or minor oral mucosal injury)

- Bleeding with trauma/surgery

- Increased bleeding after aspirin or NSAID intake

Secondary hemostasis

- Deep bleeding (e.g. muscle, hemarthrosis, soft tissue hematoma, ecchymosis)

- Bleeding with trauma/surgery

14

Which tests analyze primary hemostasis? Secondary?

Primary:

- Platelet count and smear review

- Platelet function analyzer (PFA-100)

- Von Willebrand panel (quantity and function)

Secondary:

- Prothrombin time (PT)

- Activated partial thromboplastin time (PTT)

- Thrombin time

- Factor activity assays

- Fibrinogen

15

T/F: Factor XII deficiency is not associated with bleeding?

True

- Give you prolongation in PTT, but does not cause bleeding

16

T/F: Factor XIII crosslinks fibrin and deficiencies may thus prolong PT or PTT

False

- Factor XIII crosslinks fibrin

- Deficiencies DO NOT prolong PT or PTT (but does give you bleeding)

17

What is von Willebrand Disease?

Bleeding disorder caused by deficiency or dysfunction of vWF

- Mediates initial adhesion of platelets at sites of vascular injury

- Binds/stabilizes factor VIII (8) in the circulation

Common inherited bleeding disorder

- Prevalence = 0.6-1.3% of population

18

Where is vWF made? Stored where?

2 cell types:

- Vascular endothelium: stored in secretory granules (Weibel-Palade bodies) from which it can be released by stress or drugs such as DDVP

- Megakaryocytes in the bone marrow, stored in platelet alpha-granules from which it is released following platelet activation

19

Structure of vWF?

During its biosynthesis, VWF undergoes modifications that result in the production of VWF protein arranged into multimers that vary in size (small to ultra large)

- Cleared by the liver and ADAMTS13

20

What are the different types of VWD?

Type 1: Partial quantitative deficiency of VWF

Type 2: Qualitative VWF defect (2A, 2B, 2M, 2N)

Type 3: Virtually complete deficiency of VWF

21

What will the von Willebrand panel give you?

- Quantity (antigen)

- Function (activity)

---Ristocetin (RCoF, an antibiotic) causes platelet agglutination in the presence of VWF

- VWF Ag: RCoF ratio

- Multimers

22

What is Ristocetin (RCoF)?

An antibiotic that causes platelet agglutination in the presence of VWF

23

Type 1 VWD:

- Prevalence

- Ag/RCoF results

- Multimers

- Activity

- Risks

- 75% of cases

- VWF Ag and/or RCoF under 30%

- VWF Ag: RCoF ratio is normal

- Normal multimers

- 30-50% low VWF activity; risk factor for bleeding

24

Type 2 VWD

- Subgroups

Type 2 = qualitative defects

- Low antigen +/- activity

- Abnormal VWF Ag: RCoF ratio 

25

Description of Type 2A VWD?

Unique?

Additional testing?

Decreased VWF-dependent platelet adhesion and selective deficiency of high-molecular-weight multimers (HMWM)

- Low HMWM

- Multimers are always checked when suspect type 2 VWD

26

Description of Type 2B VWD?

Unique?

Additional testing?

Increased affinity for platelet GPIb

- Low platelets

- Low HMWM

- Ristocetin induced platelet aggregation (RIPA)

27

Description of Type 2M VWD?

Unique?

Additional testing?

Decreased VWF-dependent platelet adhesion without selective deficiency of HMWM

28

Description of Type 2N VWD?

Unique?

Additional testing?

Decreased binding affinity for FVIII (8)

- Low FVIII (8)

- Assay to determine if VWF binds to FVIII

29

Ex)

- VWF: Ag 61%

- RistoCoF: 20%

- Ratio 0.3 (low)

Is this pt having type 1 or 2 VWD?

- VWF > 50% is normal

- RistoCoF of 20% is low

- Ratio 0.3 is low

So despite having some protein, it's not working very well.

- This is a type 2 disease (decreased function)

30

Ex cont'd)

- VWF: Ag 61%

- RistoCoF: 20%

- Ratio 0.3 (low)

- Multimers: absence of HMWM

- Platelets 57,000 (nl > 150,000)

- Factor VIII 64% (nl > 50%)

What disease is this?

Additional testing desired?

- Presence of HMWM

- Low platelets

This is Type 2B VWD

Additional tests would be RIPA (ristocetin induced platelet aggregation)- abnormal